BR112019022741A2 - OPTICALLY ACTIVE COMPOUND AND COMPOUND PREPARATION PROCESS - Google Patents

Abstract

the present invention relates to a process for the preparation of optically active compounds of formula x and their intermediates, wherein the variables of compound of formula x are as defined in the claims and the description.

Description

“PROCESS FOR PREPARING COMPOUND AND OPTICALLY ACTIVE COMPOUND”

Description of the Invention

[001] The present invention relates to a process for the preparation of the pyrimidinium compound containing S of formula X, according to the following reaction sequence:

Het ^{0 M 0R} H r-AC Acid / Base ⁰ _χιςΩ _ V

W 1 OR * ° --- ». oh X ¹ SO ₂ NH ₂ V

StageAHet ^ _{Stage B} Het --- * ^N 'ui iv

.. Stage C ^V Het

SAW

IO catalyst q hydrogenation __- _w HN- \ * H | 'The

Step D.

Het _{V ||}

Step E

R ¹ NCS /

Base

[002] The present invention relates to a process for the preparation of the pyrimidinium compound containing S of formula X. The pyrimidinium compounds of formula X have insecticidal properties known in WO 2014/167084. However, the process for preparing the optically active S-containing pyrimidinium compound of formula X is not described in the prior art. The present invention, to prepare the optically enriched S-containing pyrimidinium compound of formula X, is based on hydrogenation by asymmetric transfer of the cyclic imine of formulas VI. In addition, it is known from the literature that enantiomers can exhibit a different spectrum of pesticidal or insecticidal activities. It is also possible that, while a specific enantiomer shows insecticidal activity, its counterpart may be completely inactive in insects. Thus, it has become a strict requirement of any approval administration to use chiral compounds with pesticidal or insecticidal activity only in their respective active enantiomeric form.

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Thus, a process is required to prepare the optically active compound of formula X with more than 90% enantiomeric excess and with a high yield via a short route.

[003] This object is achieved by the processes described in detail below.

[004] A first aspect of the present invention relates to a process for the preparation of the pyrimidinium compound containing S of formula

X, where

THE

C * is an asymmetric carbon atom of S or R configuration;

R ¹ represents C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, or -CH2-phenyl, which are groups unsubstituted or substituted by halogen or C1-C4 alkyl;

R ² represents a 5- or 6-membered saturated, partially unsaturated or aromatic carbo- or heterocyclic ring, where the ring is unsubstituted or substituted by R ^2a ;

Het is selected from D-1, D-2 and D-3:

D-1 O-2 D_3 where

R ^a is each independently R ^a is halogen, C1C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, or phenyl;

n is 0, 1 or 2; and

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3/61 # denotes the bond in formula X;

R ^2a represents halogen, Ci-Ce haloalkyl, Ci-Ce haloalkox, OR ^C , C (= O) OR ^C , C (= O) NR ^b R ^c , phenyl, or pyridyl, which is unsubstituted or substituted by halogen , Ci-Ce haloalkyl or Ci-Ce haloalkoxy;

R ^b is hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkoxy;

R ^c is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1C ₆ cycloalkyl;

wherein two geminally bonded groups R ^and R ^b together with the atom to which they are attached can form a 3- to 7-membered, saturated, partially unsaturated or aromatic heterocyclic ring;

comprising at least the steps of:

(A) reacting a compound of formula III,

THE

JL w

Het

III in which

W is halogen, O-p-toluenesulfonyl, O-methanesulfonyl, or Otrifluoromethanesulfonyl;

Het is as defined in the compound of formula X as above;

with M ² OR ^AC where M ² is selected from lithium, sodium, potassium, aluminum, barium, cesium, calcium and magnesium; R ^AC is C (= O) C1-C4 alkyl;

to obtain the compound of formula IV,

wherein Het and R ^AC are as defined herein;

(B) hydrolysis of the compound of formula IV, as defined herein, in the presence of an acid or a base, to obtain a compound of formula V,

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Ο

OH Her

V where Het is as defined in the compound of formula IV;

(C) reacting the compound of formula V with X ² SO2NH2, where X ² is halogen, to obtain the compound of formula VI ⁰ o \\ z, ^U

N ^S \

A / °

Het ^/ ''' ^/ VI where Het is as defined in the compound of formula V, (D) hydrogenation of the compound of formula VI, in the presence of an MXLn (r | -arene) m hydrogenation catalyst, where

M is a transition metal from group VIII to group XII of the periodic table;

X is an anion;

m is 0 or 1;

Ln is Ln1 or Ln2, where

Ln1 is a chiral ligand of the formula Ln1

H

R ¹² IR ¹⁰ ^ C *

Ln1 where

C * is an asymmetric carbon atom of S or R configuration;

R ¹⁰ is OH or NH-SO2-R ¹¹ ; on what

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R ¹¹ is an aryl group unsubstituted or substituted by halogen, C1-C10 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, SO3H, or SOaNa, or C1-C10 perfluoroalkyl or R ¹³ R ¹⁴ N where R ¹³ and R ¹⁴ independently represent C1-C10 alkyl unsubstituted or substituted by CeC10 aryl, or R ¹³ and R ¹⁴ each independently represent a C6-C10 cycloalkyl group;

R ¹² independently represents aryl or C6-C10 cycloalkyl ring, where the ring is unsubstituted or substituted, independently of one another with halogen, C1-C10 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, SO3H, or SOaNa , or both R1 ² are linked together to form a 3 to 6 membered carbocyclic ring or a 5 to 10 membered ring of partially unsaturated carbocyclic ring;

Ln2 is a chiral phosphorus linker;

and a hydrogen source selected from a) hydrogen, b) mixture of N (R) 3 where R is H or C1-C6 alkyl and HCOOH, c) HCOONa or HCOOK, d) mixture of C1-Cs alcohol and t-BuOK, t-BuONa or t-BuOLi, and e) combination of two or more from a) to d);

to obtain a compound of formula VII ⁰ the

ΗΝθ

H / Γ ^Het * VII where

C * is an asymmetric carbon atom of S or R configuration;

Het is as defined in the compound of formula VI, (E) the compound of formula VII reacts, ⁰ the

HN ^ ^S xh / Γ O ^Het * VII

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6/61 where

C * is an asymmetric carbon atom of S or R configuration;

Het is as defined here;

with R ¹ NCS, where R ¹ is C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl or -Chk-phenyl, such groups not substituted or substituted by halogen or C1-C4 alkyl;

in the presence of a base, to obtain a compound of formula VIII,

S NH

SL, saw

H Het in that

C * and Het are as defined in the compound of formula VII;

R ¹ is as defined herein, (F) reacting the compound of formula VIII as defined herein, with a compound of formula IX

on what,

LG is an output group selected from halogen, OR ^U and SR ^U ; on what

R ^u is Ci-Ce alkyl or aryl, which is unsubstituted or substituted by halogen;

R ² is as defined in the compound of formula X;

to obtain the compound of formula X as defined herein.

[005] The process for preparing the compound of formula X optionally further comprises a process for preparing the compound of formula X

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7/61 formula III by at least the steps of (G) reacting a compound of formula I o

1JL W where W is as defined here, and X ¹ is halogen;

with NH (R ^Q ) (R ^P ) .HCI where R ^Q and R ^p are independently C 1 -C alkyl or C 1 -C alkoxy or R ^Q and R ^p are linked together to form a 5 to 7 ring carbocyclic or heterocyclic members;

in the presence of a base, to obtain the compound of formula II, the

JL w

R ^p where R ^Q , R ^p and W are as defined herein;

(H) reacting Het, as defined herein, with a compound of formula II, as defined herein, in the presence of an R ^L MgX ¹ or R ^G Li; where R ^L is C 1 -C 6 alkyl; X ¹ is halogen;

and a metal halide in which the metal is lithium, sodium, potassium or magnesium, to obtain the compound of formula III, the

JL w

Her in which Het and W are as defined herein.

[006] The compound of formula III can also be prepared by analogy with the methods as described herein or methods known from WO 2014/167084 or other methods known in the literature.

[007] The starting materials used in the process are either commercially available or can be prepared by methods known in the literature.

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[008] Another aspect of the present invention relates to a process for preparing the compound of formula X as defined herein, comprising one or more of the steps of (A), (B), (C), (D), (E) , (F), (G) and (H) as described herein, preferably in the sequence (H) (G) -> (A) (B) (C) (D) (E) (F) as described herein.

[009] The compounds of formula VI can be used as a versatile intermediate in the preparation of optically enriched cyclic amine derivatives of formulas VII. Therefore, it is necessary to develop a process for preparing the compound of formula VI. This objective is achieved by providing the compound of formula VI and a process for the preparation of the compound of formula VI.

[0010] Another aspect of the present invention relates to a process for preparing a compound of formula VI, as defined herein, θ o

X o

Her ^'7 VI comprising reacting the compound of formula V as hereinbefore defined, the

OH

Het ^^ with X ¹ SO2NH2, where X ¹ is a halogen, as described here in step (C).

[0011] Another aspect of the present invention relates to a compound of formula VI or salts and N-oxides thereof, θ o

Wz. ^U

Λ / °

Het ^^ ⁷ VI where Het is as defined herein.

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[0012] Compounds of formula VII, particularly optically enriched compounds of formula VII can be used as versatile intermediates for the preparation of pharmaceutical and agrochemical intermediates or active ingredients. In addition, compounds of formula VII can be used in the preparation of pesticides or heterocyclic moieties containing N, for example compounds of formula VIII or compounds of formula X which are known from WO 2014/167084 as being particularly useful for combat invertebrate pests. However, a process for preparing the optically enriched compound of formula VII, as defined herein, is not known.

[0013] Therefore, it is necessary to develop a process for the preparation of the optically active compound of formula VII, more specifically a process for the preparation of the optically active compound of formula VII with an enantiomeric excess, preferably> 70%, more preferably> 85% , more preferably> 95%. This objective is achieved by providing the optically active compound of formula VII and a process for preparing the optically active compound of formula VII with an enantiomeric excess preferably> 95%.

[0014] Another aspect of the present invention relates to a process for preparing a compound of formula VII, as defined herein,

Hei VII by hydrogenation of a compound of formula VI, as defined herein,

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10/61 as described in step (D) of this document.

[0015] Another aspect of the present invention relates to an optically active compound of formula VII or salts and N-oxides thereof.

⁰ o

ΗΝθ ^H > L ° ^Het * VII where C * and Het are as defined herein.

[0016] In addition, the optically active amine compounds of formula VIII can be used as versatile intermediate compounds for the preparation of pesticides with an amine derivative, or heterocyclic moiety containing N, for example compounds of formula X which are known to from WO 2014/167084 and is particularly useful for combating invertebrate pests. However, a process for preparing the optically active compound of formula VIII is not known.

[0017] Therefore, it is necessary to develop a process for the preparation of the optically active compound of formula VIII, more specifically a process for the preparation of the optically active compound of formula VIII with an enantiomeric excess, preferably> 80%, more preferably> 95 %.

[0018] This objective is achieved by providing the optically active compound of formula VIII and a process for the preparation of the optically active compound of formula VIII with an enantiomeric excess preferably> 95%.

[0019] Another aspect of the present invention relates to a process for preparing the compound of formula VIII, as defined herein, rL

S NH

H Het

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11/61 comprising, reacting a compound of formula VII, as defined herein, with R ¹ NCS where R ¹ is as defined herein, oo

HN ' ^S , °

^Het * VII in the presence of a base, as described in step (E) of this document.

[0020] Another aspect of the present invention relates to an optically active compound of formula VIII or salts and N-oxides thereof.

^r -n ü

S NH

Vl ^ Het ^Vl where C *, Het and R ¹ are as defined herein.

[0021] Another aspect of the present invention relates to a process for preparing the compound of formula X as defined herein, reacting the compound of formula VIII as defined herein, with a compound of formula IX as defined herein, as described in step ( F) of this document.

[0022] The molecular structure of the compound of formula X can exist in different isoelectronic formulas, each having formal positive and negative charges on different atoms, as shown below. The present invention extends to the process of preparing all isoelectronic structures representative of the compounds of formula X.

The

RÍ JL ^ R ²

THE

RÍ xL ^ R ² o

r! JL, R ²

S ^ N ^ O ’\ —p — Het

Η X \ —pr-Het

Η X \ —frHet

Η X

0 “rL, R ² o

RÍ + k J3 ²

S ^ N ^ O \ —fí-Het

Η X

S ^ N ^ O \ —fr-Het Η X

S ^ N- ^ O \ - (ΐ-Het Η X

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[0023] The "present invention", "invention" or "process of the present invention" refers to one or more of the steps (A), (B), (C), (D), (E), (F) , (G) and (H), preferably at one or more of the steps (A), (B), (C), (D), (E) and (F). The "compounds of the present invention" or "compounds according to the invention", that is, the compounds of formulas VI, VII or VIII, as defined herein, comprise the compound (s) as such, as well as salts, tautomers or Noxides thereof, if the formation of these derivatives is possible.

[0024] The term "stereoisomer (s)" encompasses both optical isomers, such as enantiomers or diastereomers, the latter existing due to more than one chirality center in the molecule, as well as geometric isomers (cis / trans isomers). The present invention or the compounds of the present invention relate to all possible stereoisomers of the compounds of the invention, that is, to single enantiomers or diastereomers, as well as mixtures thereof.

[0025] The compounds according to the invention can be amorphous or they can exist in one or more different crystalline states (polymorphs) that can have different macroscopic properties, such as stability, or show different biological properties, such as activities. The present invention relates to amorphous and crystalline compounds according to the invention, mixtures of different crystalline states of the respective compounds according to the invention, as well as amorphous or crystalline salts thereof.

[0026] The salts of the compounds according to the invention can be formed in the usual way, for example, by reacting the compound with an acid of the anion in question if the compounds according to the invention have basic functionality or by reacting acidic compounds according to with the invention with a suitable base. The salts of the compounds according to the invention are preferably agriculturally acceptable and / or veterinary salts, preferably agriculturally acceptable salts.

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[0027] The term "N-oxide" includes any compound of the present invention that has at least one tertiary nitrogen atom that is oxidized to a fraction of N-oxide.

[0028] As used here, the term "hydrogenation catalyst" encompasses homogeneous hydrogenation catalysts. It is known in the art that rhodium, ruthenium, iridium, platinum, palladium, iron or nickel form highly active catalysts. Preferred hydrogenation catalysts according to the invention are provided below.

[0029] Anions of useful acid addition salts are mainly halides such as chloride, bromide and fluoride; hydrogen sulfate, sulfate, dihydrogen phosphate, hydrogen phosphate, phosphate, nitrate, hydrogen carbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and the anions of C1-C4 alkanoic acids, preferably format, acetate, propionate and butyrate. They can be formed by reacting 0 M or MLn with a corresponding anion acid, preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid.

[0030] The groups of organic portions mentioned in the definitions above the variables are - like the term halogen - collective terms for individual listings of the individual members of the group. The prefix Cn-Cm indicates in each case the possible number of carbon atoms in the group.

[0031] "Halogen" will be understood as fluorine, chlorine, bromine and iodine.

[0032] The term "partially or fully halogenated" will be understood as 1 or more, for example, 1,2, 3, 4 or 5 or all hydrogen atoms of a given radical have been replaced by a halogen atom, in particular fluorine or chlorine.

[0033] The term "Cn-Cm alkyl" as used here (and also in Cn-Cm alkylamino, Cn-Cm dialkylamino, Cn-Cm alkylaminocarbonyl, di (Cn-Cm alkylamino) carbonyl, Cn-Cm alkylthio, Cn- alkylsulfinyl Cm and

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14/61 alkylsulfonyl C _n -Cm) refers to a branched or unbranched saturated hydrocarbon group having, for example, 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, for example methyl, ethyl, propyl , 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl , 3,3-dimethylbutyl, 1ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl , nonil and decyl and their isomers. C1-4 alkyl means, for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

[0034] The term "Cn-Cm haloalkyl" as used here (and also in Cn-Cm haloalkylsulfinyl and Cn-Cm haloalkylsulfonyl) refers to a straight-chain or branched alkyl group with carbon atoms, for example, 1 to 10, in particular 1 to 6 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups can be replaced by halogen atoms, as mentioned above, for example C1-4 haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl , trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl,

1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethylethyl, 2,2-difluoroethyl, 2-chloro-2fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2,2-trichloroethyl, pentafluoroethyl and the like. The term C1-C10 haloalkyl, in particular, comprises C1-C2, 0 fluoroalkyl which is synonymous with methyl or ethyl, where 1,2, 3, 4 or 5 hydrogen atoms are replaced by fluorine atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2difluoroethyl, 2,2,2-trifluoroethyl and pentafluoromethyl.

[0035] Likewise, "Cn-Cm alkoxy" and "Cn-Cm alkylthio" (or Cn-Cm alkylsulfenyl, respectively) refer to alkyl chain groups

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15/61 linear or branched that have carbon atoms, for example, 1 to 10, in particular 1 to 6 or 1 to 4 carbon atoms (as mentioned above) linked via oxygen (or sulfur bonds, respectively) in any bond in the alkyl group. Examples include C1-C4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy and tert-butoxy, further C1-C4 alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, and n-butylthio.

[0036] Therefore, the terms "Cn-Cm haloalkoxy" and "Cn-Cm haloalkylthio" (or Cn-Cm haloalkylsulfenyl, respectively) refer to straight or branched chain alkyl groups with carbon atoms, for example, 1 to 10, in particular 1 to 6 or 1 to 4 carbon atoms (as mentioned above) linked via oxygen or sulfur bonds, respectively, to any bond in the alkyl group, where some or all of the hydrogen atoms in those groups can be substituted by halogen atoms as mentioned above, for example, C1-C2 haloalkoxy, such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoro-methoxy, chloro-fluoro-methoxy, chloro-fluoro 1-fluoroethoxy, 2-fluoroethoxy, 2,2difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2, 2,2-trichloroethoxy and pentafluoroethoxy, still C1-C2 haloalkylthio, such as chloromethylthio, bromomethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio, dichlorofluoromethylthio, chlorodifluoromethylthio, 1-chloroethylthio, 1-bromoethylthio, 2-fluoroethylthio, 2-fluoroethylethio, 2 chloro-2fluoroethylthio, 2-chloro-2,2-difluoroethylthio, 2,2-dichloro-2-fluoroethylthio, 2,2,2trichloroethylthio and pentafluoroethylthio and the like. Likewise, the terms fluoroalkoxy C1-C2 and fluoroalkylthio C1-C2 refer to fluoroalkyl C1-C2, which is linked to the rest of the molecule via an oxygen atom or a sulfur atom, respectively.

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[0037] The term "C2-Cm alkenyl" as used herein means a branched or unbranched unsaturated hydrocarbon group having 2 am, for example 2 to 10 or 2 to 6 carbon atoms and a double bond in any position, such as ethylene, 1-propenyl, 2-propenyl, 1-methyl-ethylen, 1-butyl,

2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2- propenyl, 1-ethyl-1-propenyl, 1-ethyl-2propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl,

2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl- 2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-

3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-

3-butenyl, 1,2-dimethyl-1-butyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3dimethyl-1-butyl, 1,3-dimethyl-2- butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3- butenyl, 3,3-dimethyl-1 butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2ethyl-1-butenyl , 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

[0038] The term "C2-Cm alkynyl" as used herein refers to a branched or unbranched unsaturated hydrocarbon group having 2 am, for example 2 to 10 or 2 to 6 carbon atoms and containing at least one bond triple, such as ethinyl, propynyl, 1-butynyl, 2-butynyl and the like.

[0039] The suffix "carbonyl" in a group or "C (= O)" indicates in each case that the group is linked to the rest of the molecule through a carbonyl group C = O. This is the case, for example, of alkylcarbonyl, haloalkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl,

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17/61 haloalkoxycarbonyl.

[0040] The term "aryl" as used herein refers to a mono-, bi- or tricyclic aromatic hydrocarbon radical such as phenyl or naphthyl, in particular phenyl (also referred to as CeHs as a substituent).

[0041] The term “ring system” indicates two or more rings connected directly.

[0042] The term "Ca-Cm cycloalkyl" as used herein refers to a monocyclic ring with 3 to m members of saturated cycloaliphatic radicals, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl.

[0043] The term "5 to 10 membered partially unsaturated carbocyclic ring" as used herein refers to the partially unsaturated monocyclic or bicyclic ring containing 5 to 10 carbon atoms, for example indane.

[0044] The term "3- to 7-membered carbocyclic ring" as used herein refers to cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane rings.

[0045] The term "heterocyclic ring" refers to "3, 4, 5, 6 or 7-membered saturated, partially unsaturated or aromatic heterocyclic ring, which may contain 1, 2, 3 or 4 hetero atoms" or "containing hetero atoms ”, In which these (group (s)) heteroatom (s) are selected from N (groups substituted by N), O and S (groups substituted by S), as used here, refers to monocyclic radicals, being the monocyclic saturated, partially unsaturated or aromatic radicals (completely unsaturated). The heterocyclic radical can be attached to the rest of the molecule through a carbon ring member or through a nitrogen ring member.

[0046] Examples of saturated heterocyclyl or heterocyclic rings

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18/61 with 3, 4, 5, 6 or 7 members include: oxiranil, aziridinyl, azetidinyl, 2tetrahydrofuranyl, 3-tetrahydrofuranil, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-pyrazolidinyl, 3-pyrazolidinyl, 3-pyrazolidinyl, 3-pyrazolidinyl 5-pyrazolidinyl, 2imidazolidinyl, 4-imidazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 3isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 4-thiazolidinyl, 4-thiazolidinyl, 5-isothiazolidinyl, 1,2,4-oxadiazolidin-3yl, 1,2,4-oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl, 1,2,4triazolidin-3-yl, 1,3,4-oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl, 1,3,4-triazolidin-2il, 2-tetrahydropyranyl, 4- tetrahydropyranyl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, 2piperidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexahydropyridazinyl, 4hexahhydropyridazinyl, 2-hexahydropyrimidinil, 4-hexahydropyrimidin, piperazinil, 1,3,5-hexahidrotriazin-2-yl and 1,2,4hexahidrotriazin-3-yl, 2-morfol inyl, 3-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 1oxothiomorfolin-2-yl, 1-oxothiomorfolin-3-yl, 1,1-dioxothiomorfolin-2-yl, 1,1dioxothiomorfolin-3-yl, hexahidroazepin-1- , -2 -, - 3- or -4-yl hexahidrooxepinil, hexahidro-1,3-diazepinil, hexahidro-1,4-diazepini I, hexahidro-1,3-oxazepinil, hexahidro-1,4-oxazepinil, hexahidro- 1,3-dioxepinil, hexahydro-1,4-dioxepinil and the like.

[0047] Examples of 3, 4, 5, 6 or 7-membered partially unsaturated heterocyclyl or heterocyclic rings include: 2,3-dihydrofur-2yl, 2,3-dihydrofur-3-yl, 2,4-dihydrofur-2- yl, 2,4-dihydrofur-3-yl, 2,3-dihydrotien-2-yl, 2,3dihydrothien-3-yl, 2,4-dihydrotien-2-yl, 2,4-dihydrotien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3il, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin 3 useful, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin5-yl, 4-isoxazolin-5-yl, 2- isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5- useful, 3-isothiazolin-5yl, 4-isothiazolin-5-yl, 2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl, 2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol- 4-yl, 2,3-dihydropyrazol-5-yl, 3,4 Petition 870190110600, of 10/30/2019, p. 71/124

19/61

dihydropyrazol-1-yl, 3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3.4- dihydropyrazol-5-yl, 4,5-dihydropyrazole-1-yl, 4,5-dihydropyrazol-3-yl, 4.5- dihydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2.3- dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3.4- dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3.4- dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3.4- dihydrooxazol-4-yl, 2-, 3-, 4-, 5- or 6-di- or tetrahydropyridinyl, 3-di- or

tetrahydropyridazinyl, 4-di- or tetrahydropyridazinyl, 2-di- or tetrahydropyrimidinyl, 4di- or tetrahydropyrimidinyl, 5-di- or tetrahydropyrimidinyl, di- or tetrahydropyrazinyl,

1,3,5-di- or tetrahydrotriazin-2-yl, 1,2,4-di- or tetrahydrotriazin-3-yl, 2,3,4,5tetrahydro [1 H] azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 3,4,5,6-tetrahydro [2H] azepin2-, -3-, -4-, -5-, -6 - or -7-yl, 2,3,4,7 tetrahydro [1 H] azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 2 , 3,6,7 tetrahydro [1 H] azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, tetrahydrooxepinyl, such as 2,3,4 , 5-tetrahydro [1 H] oxepin-2-, -3-, -4-, -5-, -6- or 7-yl, 2,3,4,7 tetrahydro [1 H] oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,6,7 tetrahydro [1 H] oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, tetrahydro-1,3-diazepinyl, tetrahydro-1,4-diazepinyl, tetrahydro-1,3-oxazepinyl, tetrahydro-1,4-oxazepinyl, tetrahydro-1,3-dioxepinil and tetrahydro-1,4-dioxepinil.

[0048] Examples of 5- or 6-membered aromatic heteroaromatic or heterocyclic (hetaryl) rings are: 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1,3,4-triazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl.

[0049] The term "substituted", if not specified otherwise, refers to substituted by 1,2 or the maximum possible number of substituents.

If the substituents as defined in the compounds of formula I are more than one, then they are independent of each other the same or different if they are not

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20/61 mentioned otherwise.

[0050] The meaning of terms that are not defined here is generally known to a person skilled in the art or literature.

[0051] Preferred embodiments of the present invention are described below.

Brief Description of the Invention

[0052] In one embodiment, R ¹ is C1-C4 alkyl, C3-C6 cycloalkyl or C2-C4 alkenyl, which is not substituted or substituted by halogen.

[0053] In another embodiment, R ¹ is C1-C4 alkyl.

[0054] In another embodiment, R ¹ is methyl or ethyl.

[0055] In another embodiment, R ¹ is methyl.

[0056] In one embodiment, R ² is phenyl, pyridinyl or thiophenyl, which are unsubstituted or substituted by R ^2a .

[0057] In another embodiment, R ² is phenyl, which is unsubstituted or substituted by R ^2a , where R ^2a is halogen, C1-C6 haloalkyl, Ci-Ce haloalkox, OR ^C , C (= O) OR ^C , C (= O) NR ^b R ^c , phenyl, or pyridyl, which can be replaced by halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy.

[0058] In another embodiment, R ² is phenyl, which is unsubstituted or substituted by halogen, C1-C4 alkyl or C1-C3 haloalkyl.

[0059] In another embodiment, R ² is phenyl, which is unsubstituted or substituted by trifluoromethyl or halogen, preferably chlorine;

[0060] In another embodiment, R ² is phenyl, 3,5-dichlorophenyl, 3-trifluoromethylphenyl.

[0061] In another embodiment, R ² is phenyl.

[0062] In another embodiment, R ² is 3,5-dichlorophenyl.

[0063] In another embodiment, R ² is 3-trifluoromethylphenyl.

[0064] In one embodiment, R ^a is halogen, C1C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, or phenyl.

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[0065] In a more preferred embodiment, R ^a is halogen or C1-C4 haloalkyl.

[0066] In a more preferred embodiment, R ^a is halogen, preferably Cl.

[0067] In another preferred embodiment, R ^a is phenyl.

[0068] In one embodiment, n is 0.

[0069] In another embodiment, n is 1.

[0070] In another embodiment, n is 2.

[0071] In an embodiment of the invention, Het is D-2;

[0072] In an embodiment of the invention, Het is selected from D-1, D-2, and D-3, where

R ^a is chlorine, n is 1.

[0073] In another embodiment, Het is D-1 a, 2a-D, and D-3a:

[0074] In another embodiment, Het is D-1 a.

[0075] In another embodiment, Het is D-2a.

[0076] In another embodiment, Het is D-3a.

[0077] In an embodiment of the invention, the compound of formula X is one of the following compounds X-1 to X-6:

Compound n ^s R ¹ R ² Het X-1 ch ₃ Ph D-1 a X-2 ch ₃ Ph D-2a X-3 ch ₃ Ph D-3a X-4 ch ₃ I F D-2a

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Compound n ^s R ¹ R ² Het X-5 ch ₃ Cl D-2a X-6 ch ₂ ch ₃ Ph D-2a

[0078] In an embodiment of the invention, the compound of formula X is compound X-1.

[0079] In another embodiment of the invention, the compound of formula X is compound X-2.

[0080] In another embodiment of the invention, the compound of formula X is compound X-3.

[0081] In another embodiment of the invention, the compound of formula X is compound X-4.

[0082] In another embodiment of the invention, the compound of formula X is compound X-5.

[0083] In another embodiment of the invention, the compound of formula X is compound X-6.

[0084] In one embodiment, W is halogen, hydroxy, O-ptoluenesulfonyl, O-methanesulfonyl, or O-trifluoromethanesulfonyl.

[0085] In a preferred embodiment, W is halogen, O-ptoluenesulfonyl, O-methanesulfonyl, or O-trifluoromethanesulfonyl;

[0086] In a more preferred embodiment, W is halogen.

[0087] In another more preferred embodiment, W is hydroxy.

[0088] Preferred embodiments in relation to steps (A), (B), (C), (D), (E) and (F) of the invention are described below.

[0089] In general, the reaction steps performed in steps (A), (B), (C), (D), (E) and (F), as described in detail below, are carried out in reaction vessels usual for such reactions, the reactions being

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23/61 carried out continuously, semi-continuously or in batches.

[0090] In general, specific reactions will be carried out under atmospheric pressure. The reactions can, however, also be carried out under reduced pressure.

[0091] In general, the products obtained by any of the reaction steps (D), (E) and (F) result in enantiomeric excess. However, the enantiomeric excess can be further increased during isolation, purification, for example, crystallization of an enantiomer, as well as during or after using the product.

[0092] The temperatures and the duration of the reactions can vary in wide ranges, which the technician in the subject knows from analogous reactions. Temperatures generally depend on the reflux temperature of the solvents. Other reactions are preferably carried out at room temperature, that is, at about 25 ° C, or under cooling with ice, that is, at about 0 ° C. The end of the reaction can be monitored by methods known to a person skilled in the art, for example, thin layer chromatography or HPLC.

[0093] If not indicated otherwise, the molar ratios of the reagents, which are used in the reactions, are in the range of 0.2: 1 to 1: 0.2, preferably 0.5: 1 to 1: 0, 5, more preferably 0.8: 1 to 1: 0.8. Preferably, equimolar amounts are used.

[0094] If not indicated otherwise, the reagents can, in principle, be contacted with each other in any desired sequence.

[0095] The technician in the subject knows when the reactants (reactants) or reagents are sensitive to humidity, so the reaction must be carried out under protective gases, as under a nitrogen atmosphere, and dry solvents must be used.

[0096] The technician in the subject also knows the best treatment

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24/61 of the reaction mixture after the end of the reaction.

[0097] In the following, preferred embodiments are provided in relation to step (A) of the invention. It is to be understood that the preferred embodiments mentioned above and those yet to be illustrated below step (A) of the invention are to be understood as preferred alone or in combination with each other.

[0098] In one embodiment, M ² is selected from lithium, sodium, potassium, aluminum, barium, cesium, calcium and magnesium.

[0099] In a preferred embodiment, M ² is lithium.

[00100] In another preferred embodiment, M ² is sodium.

[00101] In another preferred embodiment, M ² is potassium.

[00102] In another preferred embodiment, M ² is aluminum.

[00103] In another preferred embodiment, M ² is barium.

[00104] In another preferred embodiment, M ² is cesium.

[00105] In another preferred embodiment, M ² is calcium.

[00106] In another preferred embodiment, M ² is Magnesium.

[00107] In one embodiment, R ^AC is C (= O) alkyl CiC _4.

[00108] In another embodiment, R ^AC is C (= O) C1 -C3 alkyl; preferably C (= O) methyl, C (= O) ethyl, C (= 0) n-propyl or C (= 0) isopropyl; more preferably C (= O) methyl.

[00109] In one embodiment, the reaction temperature in step (A) is maintained within a range of 0 to 120 ° C, preferably

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25/61 in the range of 20 to 100 ° C, more preferably in the range of 20 ° C to 60 ° C.

[00110] In one embodiment, step (A) is carried out in the absence of a solvent.

[00111] In another embodiment, step (A) is carried out in a solvent.

[00112] Suitable solvents include water and aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and light petroleum; aromatic hydrocarbons such as toluene, o-, m- and p-xylene; halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol; C2-C4 alkandiois, such as ethylene glycol or propylene glycol; ether alkanols such as diethylene glycol; carboxylic esters such as ethyl acetate; N-methylpyrrolidone; dimethylformamide; dimethyl acetamide; and ethers, including open chain and cyclic ethers, especially diethyl ether, methyl tert-butyl ether (MTBE), 2-methoxy-2-methylbutane, cyclopentyl methyl ether, 1,4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, in particular tetrahydrofuran, MTBE and 2-methyltetrahydrofuran. Mixtures of said solvents can also be used.

[00113] In a preferred embodiment, the solvent is selected from water, C2-C6 alkanediols, C1-C6 haloalkanes, halobenzene, carboxylic esters, N-methylpyrrolidone; dimethylformamide; dimethyl acetamide and ethers, including open-chain and cyclic ethers, or a mixture of the two or more of them.

[00114] In another preferred embodiment, the solvent is selected from dimethylformamide, tetrahydrofuran, 2methyltetrahydrofuran, N-methylpyrrolidone, dimethyl acetamide or a mixture of the two or more of the same.

[00115] In one embodiment, the volume ratio of the

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26/61 compound of formula III for solvent is in the range of 1:30 to 1: 0.

[00116] In another embodiment, the volume ratio of the compound of formula III to solvent is in the range of 1:20 to 1:10.

[00117] In a preferred embodiment, the volume ratio of the compound of formula III to solvent is in the range of 1:10 to 1: 0.

[00118] In the following, preferred embodiments are provided in relation to step (B) of the invention. It is to be understood that the preferred embodiments mentioned above and those yet to be illustrated below step (B) of the invention are to be understood as preferred alone or in combination with one another.

[00119] In one embodiment, step (B) is carried out in the presence of an acid;

[00120] In an embodiment, suitable acids are, in general, inorganic acids, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, perchloric acid or a mixture of one or more of them.

[00121] In a preferred embodiment, the acid is hydrochloric acid, sulfuric acid, phosphoric acid, hydroiodic acid or a mixture of one or more of them.

[00122] In another embodiment, suitable acids are Lewis acids, such as boron tri fluoride, aluminum tri chloride, iron (III) chloride, tin (IV) chloride, titanium (IV) chloride and and chloride zinc (II).

[00123] In another embodiment, suitable acids are organic acids in general, such as formic acid, C1-8 alkyl (COOH) _y , or C1-8 haloalkyl (COOH) _y , where y is 1 or 2; CH3SO3H, citric acid, oxalic acid, p-toluenesulfonic acid acetic acid, propionic acid, oxalic acid, toluene sulfonic acid, benzene sulfonic acid, camphor sulfonic acid, citric acid, and trifluoro acetic acid, or mixture of one or more of

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27/61 same.

[00124] In a preferred embodiment, the acid is C1-8 alkyl (COOH) _y , C1-8 haloalkyl (COOH) _y , where y is 1 or 2, CH3SO3H, citric acid, oxalic acid, p-toluenesulfonic, or mixture of two or more of them.

[00125] In another embodiment, the acid in step (B) is selected from hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, hydroiodic acid, C1-8 alkyl (COOH) _y , C1-8 haloalkyl - (COOH) _y , CH3SO3H, citric acid, oxalic acid, p-toluenesulfonic acid, or a mixture of two or more of them; where y is 1 or 2.

[00126] In a particularly preferred embodiment, the acid in step (B) is hydrochloric acid.

[00127] Acids are generally used in equimolar amounts; however, they can also be used in catalytic amounts, in excess or, if appropriate, as a solvent.

[00128] In another embodiment, step (B) is carried out in the presence of an acid and a buffer.

[00129] The buffers include aqueous and non-aqueous buffers and are preferably non-aqueous buffers. Preferred buffers include acetate, phosphate or formate based buffers, for example, sodium acetate, potassium hydrogen phosphate, potassium dihydrogen phosphate, or ammonium formate. In one embodiment, step (B) is performed in the presence of a base;

[00130] Suitable bases are, in general, inorganic compounds, such as alkali metal hydroxides and alkaline earth metals, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal oxides and alkali metals earthy, like oxide

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28/61 lithium, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate, and also

[00131] In a particularly preferred embodiment, the base is selected from alkali metal and alkaline earth metal hydroxides, in particular from the group consisting of lithium hydroxide, sodium hydroxide, magnesium hydroxide, hydroxide potassium and calcium hydroxide.

[00132] In another particularly preferred embodiment, the base is selected from oxides of alkali metals and alkaline earth metals, in particular from the group consisting of lithium oxide, sodium oxide, calcium oxide and oxide of magnesium.

[00133] The bases are generally used in equimolar quantities; however, they can also be used in catalytic amounts or in excess.

[00134] In one embodiment, the temperature of the hydrolysis reaction in step (B) is maintained within a range of 0 to 120 ° C, preferably in the range of 20 to 100 ° C, more preferably in the range of 20 ° C to 60 ° C.

[00135] In one embodiment, the hydrolysis in step (B) is carried out in the absence of a solvent.

[00136] In another embodiment, the hydrolysis in step (B) is carried out in a solvent.

[00137] Suitable solvents include water and aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and light petroleum; aromatic hydrocarbons such as toluene, o-, m- and p-xylene;

halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol

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29/61 and tert-butanol; C2-C4 alkanediols, such as ethylene glycol or propylene glycol; ether alkanols such as diethylene glycol; carboxylic esters such as ethyl acetate; N-methylpyrrolidone; dimethylformamide; and ethers, including open-chain and cyclic ethers, especially diethyl ether, methyl-tert-butyl-ether (MTBE), 2-methoxy-2methylbutane, cyclopentylmethylether, 1,4-dioxane, tetrahydrofuran and 2methyltetrahydrofuran, in particular tetrahydrofuran, MTB 2methyltetrahydrofuran. Mixtures of said solvents can also be used.

[00138] In another embodiment, the solvent is selected from C1-C6 alcohol, water, C2-C6 alkanediols, carboxylic esters, N-methylpyrrolidone, dimethylformamide, and ethers, including open-chain and cyclic ethers, or a mixture of two or more of them.

[00139] In another embodiment, the solvent is selected from water, dimethylformamide, N-methylpyrrolidone, methyl-tert-butyl-ether, methanol, ethanol, isopropanol or a mixture of two or more of them.

[00140] Preferred solvents are protic solvents, preferably alcohols selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol.

[00141] In a preferred embodiment, the solvent is a C1-C4 alcohol, in particular methanol.

[00142] In one embodiment, the volume ratio of the compound of formula VI to solvent is in the range of 1:30 to 1: 0.

[00143] In another embodiment, the volume ratio of the compound of formula VI to solvent is in the range of 1:20 to 1:10.

[00144] In a preferred embodiment, the volume ratio of the compound of formula VI to solvent is in the range of 1:10 to 1: 0.

[00145] In the following, preferred embodiments are provided in relation to step (C) of the invention. It should be understood that the

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Preferred embodiments mentioned above and those yet to be illustrated below step (C) of the invention are to be understood as preferred alone or in combination with each other.

[00146] In one embodiment, X ¹ is halogen selected from Cl, Br, I and F.

[00147] In a preferred embodiment, X ^{1 is} C.

[00148] In another preferred embodiment, X ¹ is Br.

[00149] In another preferred embodiment, X ¹ is I.

[00150] In another preferred embodiment, X ¹ is F.

[00151] In one embodiment, step (C) is carried out in the presence of an acid.

[00152] In one embodiment, suitable acids are, in general, inorganic acids, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, perchloric acid or a mixture of one or more of them.

[00153] In a preferred embodiment, the acid is hydrochloric acid, sulfuric acid, phosphoric acid, hydroiodic acid or a mixture of one or more thereof.

[00154] In another embodiment, suitable acids are Lewis acids, such as boron tri fluoride, aluminum tri chloride, iron (III) chloride, tin (IV) chloride, titanium (IV) chloride and chloride zinc (II).

[00155] In another embodiment, suitable acids are in general organic acids such as formic acid, C1-8 alkyl (COOH) _y , or C1-8 haloalkyl (COOH) _y , where y is 1 or 2 ; CH3SO3H, citric acid, oxalic acid, p-toluenesulfonic acid acetic acid, propionic acid, oxalic acid, toluene sulfonic acid, benzene sulfonic acid, camphor sulfonic acid, citric acid, and trifluoro acetic acid, or mixture of one or more of the same .

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[00156] In a preferred embodiment, the acid is C 1 -C 8 -alkyl (COOH) _y , C 1 -C 8- haloalkyl (COOH) _y , where y is 1 or 2, CH 3 SO 3 H, citric acid, oxalic acid, acid p-toluenesulfonic, or mixture of two or more of them.

[00157] In another embodiment, the acid in step (C) is selected from hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, hydroiodic acid, C1-8 alkyl (COOH) _y , C1-8 haloalkyl - (COOH) _y , CH3SO3H, citric acid, oxalic acid, p-toluenesulfonic acid, or a mixture of two or more of them; where y is 1 or 2.

[00158] In a particularly preferred embodiment, the acid in step (C) is p-toluenesulfonic acid.

[00159] Acids are generally used in equimolar amounts; however, they can also be used in catalytic amounts, in excess or, if appropriate, as a solvent.

[00160] In another embodiment, step (C) is carried out in the presence of an acid and a buffer.

[00161] The buffers include aqueous and non-aqueous buffers and are preferably non-aqueous buffers. Preferred buffers include acetate, phosphate or formate based buffers, for example, sodium acetate, hydrogen potassium phosphate, potassium dihydrogen phosphate, or ammonium formate.

[00162] In one embodiment, the reaction temperature in step (C) is kept within a range of 0 to 150 ° C, preferably in the range of 20 to 120 ° C, more preferably in the range of 30 ° C to 100 ° C.

[00163] In one embodiment, the hydrolysis in step (C) is carried out in the absence of a solvent.

[00164] In another embodiment, hydrolysis in the step

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32/61 (C) is carried out in a solvent.

[00165] Suitable solvents include water and aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and light petroleum; aromatic hydrocarbons, such as toluene, chlorobenzene, o-, m- and p-xylene; halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol; C2-C4 alkanediols, such as ethylene glycol or propylene glycol; ether alkanols such as diethylene glycol; carboxylic esters such as ethyl acetate; N-methylpyrrolidone; dimethylformamide; and ethers, including open-chain and cyclic ethers, especially diethyl ether, methyl-tert-butyl-ether (MTBE), 2-methoxy-2-methylbutane, cyclopentylmethyl, 1,4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, in particular tetrahydrofuran, MTBE and 2-methyltetrahydrofuran. Mixtures of said solvents can also be used.

[00166] In another embodiment, the solvent is selected from C1-C6 alcohol, water, C2-C6 alkanediols, carboxylic esters, N-methylpyrrolidone, dimethylformamide, and ethers, including open-chain and cyclic ethers, or a mixture of two or more of them.

[00167] In another embodiment, the solvent is selected from water, dimethylformamide, N-methylpyrrolidone, methyl-tert-butyl-ether, methanol, ethanol, isopropanol or a mixture of two or more of them.

[00168] Preferred solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and light petroleum; aromatic hydrocarbons, such as toluene, chlorobenzene, 0-, m- and p-xylene ;.

[00169] In a particularly preferred embodiment, the solvent is toluene.

[00170] In one embodiment, the volume ratio of the compound of formula V to solvent is in the range of 1:30 to 1: 0.

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[00171] In another embodiment, the volume ratio of the

compound of formula V for solvent is in the range of 1:20 to 1:10.

[00172] In a preferred embodiment, the ratio in

volume of the compound of formula V for solvent is in the range of 1:10 to 1: 0.

[00173] Below, embodiments are provided

preferred over step (D) of the invention. It is to be understood that the preferred embodiments mentioned above and those yet to be illustrated below step (D) of the invention are to be understood as preferred alone or in combination with each other.

[00174] In one embodiment, the hydrogen source is

selected from b) mixture of N (R) 3, where R is H or C 1 -C and alkyl HCOOH, c) HCOONa and d) mixture of isopropyl alcohol and í-BuOK or í-BuONa, or í-BuOLi;

[00175] In one embodiment, the hydrogen source is

a mixture of N (R) 3 and HCOOH.

[00176] In one embodiment, R is H; [00177] In another embodiment, R is Ci-Ce alkyl [00178] In another embodiment, R is C1-C4 alkyl, as

such as methyl, ethyl, isopropyl, n-propyl, tert-butyl.

[00179] In a preferred embodiment, R is H, ethyl,

isopropyl or tec-butyl.

[00180] In a more preferred embodiment, R is H or

ethyl.

[00181] In a more preferred embodiment, R is ethyl. [00182] In one embodiment, the volume ratio of

N (R) 3 for HCOOH is in the range of 1: 2 to 1:10.

[00183] In a preferred embodiment, the ratio in

volume of N (R) 3 for HCOOH is in the range of 1: 1 to 1: 4.

[00184] In a more preferred embodiment, the reason

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34/61 by volume of N (R) 3 for HCOOH is in the range of 1: 1 to 1: 3.

[00185] In another embodiment, the hydrogen source is HCOONa.

[00186] In another embodiment, the hydrogen source is HCOOK.

[00187] In another embodiment, the hydrogen source is a mixture of isopropyl alcohol and i-BuOK.

[00188] In another embodiment, the hydrogen source is a mixture of isopropyl alcohol and i-BuONa.

[00189] In one embodiment, m is 0.

[00190] In one embodiment, m is 1.

[00191] In one embodiment, the hydrogenation catalyst is MXLn (q-arene) m where m is 1 η-arene is an aryl ring which is unsubstituted or substituted by C1-C4 alkyl.

[00192] In one embodiment, the hydrogenation catalyst is MXLn (q-arene) m, where m is 1 and q-arene is selected from benzene, p-cymene, mesitylene, 2,4,6- triethylbenzene, hexamethylbenzene, anisol, 1,5-cyclooctadiene, cyclopentadienyl (Cp), norbornadiene and pentamethylcyclopentadienyl (Cp *).

[00193] In one embodiment, the hydrogenation catalyst is MXLn (q-arene) m, where m is 1 and q-arene is selected from benzene, p-cymene, mesitylene, 2,4,6- triethylbenzene, hexamethylbenzene, anisol, 1,5-cyclooctadiene, cyclopentadienyl (Cp) and pentamethylcyclopentadienyl (Cp *).

[00194] In another embodiment, the hydrogenation catalyst is MXLn (q-arene) m, where m is 1 and q-arene is selected from cyclopentadienyl (Cp) and pentamethylcyclopentadienyl (Cp *).

[00195] In another embodiment, the catalyst for

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35/61 hydrogenation is MXLn (q-arene) m, where m is 1 and η-arene is selected from cyclopentadienyl (Cp).

[00196] In another embodiment, the hydrogenation catalyst is MXLn (q-arene) m, where m is 1 and q-arene is pentamethylcyclopentadienyl (Cp *).

[00197] In another embodiment, the hydrogenation catalyst is MXLn (q-arene) m where m is 1 and q-arene is selected from benzene, p-cymene, mesitylene, 2,4,6-triethylbenzene , hexamethylbenzene, anisole and 1,5-cyclooctadiene.

[00198] In one embodiment, X is an anion formed by reacting M or MLn with an acid from the corresponding anion, preferably hydrochloric acid, hydrobromic acid, hydroiodic acid, tetrafluoroboric acid or hexafluorophosphoric acid.

[00199] In another embodiment, X is selected from halides, hexafluorosilicate, hexafluorophosphate, benzoate, sulfonate and the anions of Ci-Ce alkanoic acids, preferably format, acetate, propionate and butyrate.

[00200] In another embodiment, X is halide selected from chloride, bromide and iodide.

[00201] In another embodiment, X is chloride or bromide.

[00202] In another embodiment, X is chloride.

[00203] In another embodiment, X is tetrafluoroborate.

[00204] In another embodiment, Ln is Ln1 where R ¹⁰ is NH-SO2-R ¹¹ , and where R ¹² and R ¹¹ are independently unsubstituted or substituted aryl.

[00205] In another embodiment, Ln is Ln1 where R ¹⁰ is NH-SO2-R ¹¹ , and where R ¹² and R ¹¹ are independently substituted aryl.

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[00206] In another embodiment, Ln is Ln1 where R ¹⁰ is NH-SO2-R ¹¹ , and where R ¹² and R ¹¹ are independently unsubstituted aryl.

[00207] In another embodiment, Ln is Ln1 where R ¹⁰ is NH-SO2-R ¹¹ , and where R ¹¹ is substituted aryl and R ¹² is C6-C10 cycloalkyl.

[00208] In another embodiment, Ln is Ln1 and where R ¹⁰ is NH-SO2-R ¹¹ ; and where R ¹¹ is substituted aryl and R ¹² is unsubstituted aryl.

[00209] In another embodiment, Ln is Ln1 and where R ¹⁰ is NH-SO2-R ¹¹ ; and where R ¹¹ is substituted aryl and R ¹² is substituted aryl.

[00210] In another embodiment, Ln is Ln1 where R ¹⁰ is NH-SO2-R ¹¹ , and where R ¹¹ is unsubstituted or substituted aryl and both R ¹² are linked together to form a carbocyclic ring with 3 6-membered or partially unsaturated carbocyclic ring with 5 to 10 members.

[00211] In another embodiment, MXLn (q-arene) m is MXLnl (q-arene) m where R ¹⁰ is NH-SO2-R ¹¹ ; and R ¹² and R ¹¹ are independently phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, SO3H, and SOsNa.

[00212] In another embodiment, MXLn (q-arene) m is MXLnl (q-arene) m where X is halide; R ¹² is independently phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl or 4-methoxyphenyl; R ¹⁰ is NH-SO2-R ¹¹ , and SO2-R ¹¹ is p-toluenesulfonyl, methanesulfonyl, 4-benzenesulfonyl, 4trifluoromethylphenyl-sulfonyl or pentafluorophenyl-sulfonyl.

[00213] In another embodiment, Ln is Ln1 where R ¹⁰ is OH and R ¹² is unsubstituted or substituted aryl.

[00214] In another embodiment, Ln is Ln1 where R ¹⁰ is OH and R ¹² is substituted aryl.

[00215] In another embodiment, Ln is Ln1 where R ¹⁰ is OH and R ¹² is unsubstituted aryl.

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[00216] In another embodiment, Ln is Ln1 where R ¹⁰ is OH and R ¹² is Ce-Cw cycloalkyl.

[00217] In another embodiment, Ln is Ln1 where R ¹⁰ is OH and both R ¹² are linked together to form a 3 to 6 membered carbocyclic ring or a 5 to 10 membered unsaturated carbocyclic ring.

[00218] In another embodiment, Ln1 is supported on silica gel, dendrimers, polystyrenes or mesoporous silica foam, for example, as described in Haraguchi, N., Tsuru, K., Arakawa, Y., Isuno, S. Org. Biomol. Chem. 2009, 7, 69.

[00219] In one embodiment, M is rhodium, ruthenium, iridium, platinum, palladium, iron or nickel.

[00220] In another embodiment, M is rhodium, ruthenium, iridium, or platinum.

[00221] In another embodiment, M is rhodium, ruthenium, or platinum.

[00222] In another embodiment, M is rhodium, iridium, or platinum.

[00223] In another embodiment, M is rhodium, ruthenium or iridium.

[00224] In another embodiment, M is rhodium or ruthenium.

[00225] In another embodiment, M is rhodium or iridium.

[00226] In another embodiment, M is ruthenium or iridium.

[00227] In another embodiment, M is palladium, iron or nickel.

[00228] In another embodiment, M is palladium or nickel.

[00229] In another embodiment, M is iron or nickel.

[00230] In another embodiment, M is palladium or iron.

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[00231] In a preferred embodiment, M is rhodium.

[00232] In another preferred embodiment, M is ruthenium.

[00233] In another preferred embodiment, M is iridium.

[00234] In another preferred embodiment, M is palladium.

[00235] In another preferred embodiment, M is iron.

[00236] In another preferred embodiment, M is nickel.

[00237] In another preferred embodiment, M is platinum.

[00238] In another embodiment, m is 1 and ΜΧΙ_η (ηareno) m has the formula MXLnCp *, where M is rhodium, ruthenium, iridium, platinum, palladium, iron or nickel.

[00239] In another embodiment, Ln is Ln2, which is a chiral phosphorus linker.

[00240] In another embodiment, the chiral phosphorus linker Ln2 is selected from chiral ligands of monodentate or bidentate, phosphine or phosphite.

[00241] In another embodiment, the chiral phosphorus linker is selected from the linkers listed below in Table A or selected from their corresponding enantiomers.

Table A: where Cy = cyclohexyl and Ph = phenyl

Mr. No. Structure Name 1. oe ^ (end, end) -DIPAMP

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Mr. No. Structure Name 2. d — 1 H P (Ph) 2 (end, end) -NORPHOS 3. QP H ₃ C '° F 0' ^CH 3 σ ^ρ ύ fS.SJ-DIPAMP 4. fS.SJ-BPPM 5 ^ ° J ^ P (R) 2 ^oJ ^ P (R) 2 fS.SJ-DIOP: R = Ph fS.SJ-Cy-DIOP: R = Cy fS.SJ-MOD-DIOP: R = 3,5- (CH ₃ ) 2-4- (CH ₃ O) C6H2 6 OCXp (r) 2 At ^{p (r) 2} fSJ-BINAP: R = Ph / SJ-TolBINAP: R = 4-CH ₃ C ₆ H4 / SJ-XylBINAP: R = 3,5- (CH ₃ ) 2-C ₆ H ₃ 7 PR ¹ x ^ S ^ ^p ( ^r ) 2 p <L _{P (Rh} fSJ-BICHEP: R = Cy; R ¹ = CH ₃ fSJ-BIPHEMP: R = Ph; Ri = CH ₃ fSJ-BIPHEP: R = Ph; R® OCH ₃

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Mr. No. Structure Name 8 C ^and Cy-P \ PPh2 COX fS.SJBCPM: X = OC (CH ₃ ) 3 /S.SJ-MCCPM: X = NHCH ₃ 9 Ç ^ PPh2 A ~ PPh2 fS.SJ-BDPP 10 Ph2P PPh2 V fS.SJ-PYRPHOS 11 cpb R R fS.SJ-Me-BPE: R = CH ₃ fS, SJ-Et-BPE: R = C2H5 fS, SJ-iPr-BPE: R = iso- (CH ₃ ) 3 12 R ΥΎ ^ρΓ ^ ^κ LI>' ^R ^^ P ^ \ ('S.SJ-Me-DuPhos: R = CH ₃ (S, SJ-Et- DuPhos: R = C2H5 ('S.SJ-iPr- DuPhos: R = iso- (CH ₃ ) 3 13 OMe MeO ^ A ^ Ph Ta MeO ^xS >p'PPh2 MeO.zL.PPh2 1 A MeO ^ A ^ Ph OMe fSJ-o-Ph-HexaMeO-BIPHEP 14 oxpx 1 p ^p Ύ oA xo fS.SJBINAPHANE

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Mr. No. Structure Name 15 Ph2P \> H < ^H / \ „> PPh2 (f, f) -BCIP 16 O., / ^. Pp _h2 VoX / ^PPh2 (f, S, S, f) -DIOP * 17 P (Rh Fe p (R-) 2 Φ (fí) - ('SJ-Josiphos: R = Cy, R ’= Ph (f) -fSJ-PPF-t-Bu ₂ : R = t-Bu, R '= Ph (fi) - / S) -Xyliphos: R = 3,5-Me ₂ -C6H3, R = Ph (fi) - / SJ-Cy ₂ PF-PCy ₂ : R = R '= Cy 18 ÇHEt2 VTJ) - ^PPh2 Fe —pph2 CHEt2 / S, SJ-FerroPHOS 19 Me _{Z /} Ph / A) - ^PPh2 Fe ÍOr) - ^pph2 \ —Ph Me * FERRIPHOS 20 R „.. p p ... CH ₃ H ₃ C ^V R (S, S) - BisP * ('S.SJ-tBu-BisP *: R = tBu ('S.SJ-Ad-BisP *: R = 1-adamantyl

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Mr. No. Structure Name ('S.SJ-Cy-BisP *: R = Cy 21 f-Bu t-BÜ fS.S.fí.fíJ-TangPhos 22 υυ ^^ ^ρρΐη2 γΈΥ JJPPh2 ('SJ- [2,2] -PHENOPHOS 23 .xx / XzPh Γ Jf j (pPh2 L · JL xW ^^^ Ph (SJ-Ph-o-NAPHOS 24 <5 — OPPh2 V 'y'OPPh2 (f) -spirOP 25 4- ° <0 k.OPPh2 θΖ'χ / 'OPPh2 x ^ó DIMOP 26 Γ jT JfoPPh2 L 1 OPPh2 BINAPO: FUH (SJ-Ph-o-BINAPO; R = Ph 27 0 P (R) 2 P (R) 2 ('S> Cy, Cy-oxoProNOP: R = Cy ('SJ-Cp, Cp-oxoProNOP: R = Cp 28 Ph Ph O ^/ \ -Me II PPh2 PPh2 (1 child, 2SJ-DPAMPP

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Mr. No. Structure Name 29 {//// - ΝΗΡΑΓ2 NHPAr2 Here/ (f) -BDPAB: Ar = Ph (ph-Xyl-BDP: Ar = 3.5-Me ₂ C6H ₃ 30 NHPPh2 NHPPh2 HERE/ (f) -Hs-BDPAB

[00242] In another embodiment, the chiral phosphorus ligand is selected from (F?) - BINAP, (Sj-BINAP, (ft) TolBINAP, (S) TolBINAP, (fl, fl) -DIPAMP, ( S, SJ-DIPAMP, (fl) - (SJ-Josiphos, or selected from their corresponding enantiomers.

[00243] In one embodiment, the molar ratio of the compound of formula III to MXLn (q-arene) m is in the range of 1: 0.0001 to 1: 0.001.

[00244] In a preferred embodiment, the molar ratio of the compound of formula III to MXLn (q-arene) m is in the range of 1: 0.001 to 1: 0.01.

[00245] In a more preferred embodiment, the molar ratio of the compound of formula III to MXLn (q-arene) m is in the range of 1: 0.001 to 1: 0.05.

[00246] In one embodiment, the reaction temperature of the hydrogenation in step (D) is kept within a range of 0 to 120 ° C, preferably in the range of 0 to 85 ° C, preferably in the range of 20 to 85 ° C, more preferably in the range of 20 ° C to 50 ° C, also more preferably in the range of 0 ° C to 30 ° C, also more preferably at 0 ° C.

[00247] In one embodiment, the hydrogenation reaction in step (A) is carried out at a temperature below 0 ° C.

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[00248] In one embodiment, hydrogenation in step (D) is carried out in the absence of a solvent.

[00249] In another embodiment, the hydrogenation in step (D) is carried out in a solvent.

[00250] Suitable solvents include water and aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and light petroleum; aromatic hydrocarbons such as toluene, o-, m- and p-xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, 1,2dichloroethane and chlorobenzene; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol; C2-C4 alkanediols, such as ethylene glycol or propylene glycol; ketones like acetone, 2-butanone; ether alkanols such as diethylene glycol; carboxylic esters such as ethyl acetate; N-methylpyrrolidone; dimethylformamide; dimethyl acetamide; and ethers, including open-chain and cyclic ethers, especially diethyl ether, methyl-tert-butyl-ether (MTBE), 2-methoxy-2methylbutane, cyclopentylmethylether, 1,4-dioxane, tetrahydrofuran and 2methyltetrahydrofuran, in particular tetrahydrofuran, MTB 2methyltetrahydrofuran. Mixtures of said solvents can also be used.

[00251] In a preferred embodiment, the solvent is selected from water, C2-C6 alkanediols, C1-C6 haloalkanes, halobenzene, carboxylic esters, N-methylpyrrolidone; dimethylformamide; toluene, dimethyl acetamide and ethers, including open chain and cyclic ethers, or a mixture of the two or more of them.

[00252] In another preferred embodiment, the solvent is selected from water, dimethylformamide, tetrahydrofuran, Nmethylpyrrolidone, dimethyl acetamide or a mixture of the two or more of them.

[00253] In one embodiment, the volume ratio of the compound of formula VI to the solvent is in the range of 1:40 to 1: 0.

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[00254] In another embodiment, the volume ratio of the compound of formula VI to the solvent is in the range of 1:30 to 1: 5.

[00255] In a preferred embodiment, the volume ratio of compound of formula VI to the solvent is in the range of 1:20 to 1:10, preferably 1: 1.

[00256] The reaction times in step (D) can vary over a wide range. Preferred reaction times are in the range of 5 minutes to 1 day, preferably 15 minutes to 6 hours, more preferably in the range of 15 minutes to 3 hours, for example, 1 to 2 hours.

[00257] In one embodiment, step (D) can be performed in the presence of N (R ^s ) 4X ^a surfactants in which R ^s is independently C1-C22 alkyl, cycloalkyl or C1-C22 aryl which is not substituted or substituted by halogen, and X ^a is chlorine, bromine, iodine, hydrogen sulfate, phosphate, hexafluoro-phosphate, acetate, benzoate or tetrafluoroborate.

[00258] It is still preferred that the reaction be carried out in an atmosphere of inert or protective gas, for example, under nitrogen or argon.

[00259] It is still preferred that the reaction be carried out under reduced pressure.

[00260] In another embodiment, the reaction is carried out under a hydrogen atmosphere.

[00261] In a preferred embodiment, the compound of formula VII is obtained in step (D) in> 80% enantiomeric excess.

[00262] In the following, preferred embodiments are provided in relation to step (E) of the invention. It is to be understood that the preferred embodiments mentioned above and those yet to be illustrated below step (E) of the invention are to be understood as preferred alone or in combination with each other.

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[00263] In one embodiment, step (E) is performed in the presence of a base;

[00264] Suitable bases are, in general, inorganic compounds, such as alkali metal hydroxides and alkaline earth metals, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal oxides and alkali metals earthy substances, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal oxides, such as sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, tert -sodium butoxide, and potassium tert-butoxide, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate, and also alkali metal bicarbonates, such as sodium bicarbonate, in addition , organic bases, for example, tertiary amines, such as trimethylamine, triethylamine, triisopropylethylamine, N-methylmorpholine and Nmethylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4dimethylaminopyridine, and also bicyclic amines, such as 1,8Diazabicyclo [5.4.0] undec-7-ene and 1,4-diazabicyclo [2.2.2] octane.

[00265] In a particularly preferred embodiment, the base is selected from alkali metal and alkaline earth metal hydroxides, in particular from the group consisting of lithium hydroxide, sodium hydroxide, magnesium hydroxide, hydroxide potassium and calcium hydroxide.

[00266] In another particularly preferred embodiment, the base is selected from oxides of alkali metals and alkaline earth metals, in particular from the group consisting of lithium oxide, sodium oxide, calcium oxide and oxide of magnesium.

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[00267] In another particularly preferred embodiment, the base is selected from alkali metal and alkaline earth metal carbonates, in particular from the group consisting of lithium carbonate and calcium carbonate.

[00268] In another particularly preferred embodiment, the base is selected from alkali metal bicarbonates and is preferably sodium bicarbonate.

[00269] In another particularly preferred embodiment, the base is selected from alkali metal alkyls, in particular from the group consisting of methyl lithium, butyl lithium and phenyl lithium.

[00270] In another particularly preferred embodiment, the base is selected from alkylmagnesium halides and is preferably isopropylmagnesium chloride.

[00271] In another particularly preferred embodiment, the base is selected from trimethylamine, triethylamine, triisopropylethylamine, n-tributylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines .

[00272] In a more particularly preferred embodiment, the base is n-tributylamine or triethylamine.

[00273] The bases are generally used in equimolar quantities; however, they can also be used in catalytic amounts, in excess or, if appropriate, as a solvent.

[00274] In one embodiment, the hydrolysis reaction temperature in step (C) is maintained within a range of 0 to 120 ° C, preferably in the range of 20 to 85 ° C, more preferably in the range of 20 ° C to 60 ° C.

[00275] In one embodiment, step (E) is performed

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[00276] In another embodiment, step (E) is carried out in a solvent.

[00277] Suitable solvents include water and aliphatic hydrocarbons, such as hexane, cyclohexane and petroleum ether; aromatic hydrocarbons such as toluene, o-, m- and p-xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, 1,2-dichloroethane and chlorobenzene; alcohols such as methanol, ethanol, n-propanol, isopropanol, nbutanol, iso-butanol and tert-butanol; C2-C4 alkanediols, such as ethylene glycol or propylene glycol; ether alkanols such as diethylene glycol; ketones like acetone or 2-butanone; carboxylic esters such as ethyl acetate; carboxylic amides such as N-methylpyrrolidone; dimethylformamide; and ethers, including open chain and cyclic ethers, especially diethyl ether, methyl tert-butyl ether (MTBE), 2-methoxy-2-methylbutane, cyclopentyl methyl ether, 1,4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, in particular tetrahydrofuran, MTBE and 2-methyltetrahydrofuran. Mixtures of said solvents can also be used.

[00278] In another embodiment, the solvent is selected from C1-C6 alcohol, water, C2-C6 alkanediols, carboxylic esters, N-methylpyrrolidone, dimethylformamide, and ethers, including open-chain and cyclic ethers, or a mixture of two or more of them.

[00279] In another embodiment, the solvent is selected from water, dimethylformamide, N-methylpyrrolidone, methyl-tert-butyl-ether, methanol, ethanol, isopropanol or a mixture of two or more of them.

[00280] Preferred solvents are protic solvents, preferably alcohols selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol.

[00281] In a preferred embodiment, the solvent is

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[00282] In one embodiment, the volume ratio of the

compound of formula VII for solvent is in the range of 1:30 to 1: 0.

[00283] In another embodiment, the volume ratio of the

compound of formula VII for solvent is in the range of 1:20 to 1: 5.

[00284] In a preferred embodiment, the ratio in

volume of the compound of formula VII for solvent is in the range of 1:20 to

1:10.

[00285] Below, embodiments are provided

preferred over step (F) of the invention. It is to be understood that the preferred embodiments mentioned above and those yet to be illustrated below step (F) of the invention are to be understood as preferred alone or in combination with one another.

[00286] In one embodiment, LG is OR ^U ; [00287] In another embodiment, LG is SR ^U ; [00288] In one embodiment, R ^u is non-Ci-Ce alkyl

substituted;

[00289] In another embodiment, R ^u is Ci-Ce alkyl, which

is replaced by halogen;

[00290] In another embodiment, R ^u is non-aryl

substituted;

[00291] In another embodiment, R ^u is aryl which is

replaced by halogen;

[00292] In one embodiment, the temperature of the

The reaction in step (F) is kept within a range of 20 to 130 ° C, preferably in the range of 20 to 100 ° C, more preferably in the range of 70 ° C to 100 ° C.

[00293] In one embodiment, step (F) is performed

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[00294] In another embodiment, step (F) is carried out in a solvent.

[00295] Suitable solvents include aliphatic hydrocarbons such as hexane, heptane, cyclohexane and petroleum ether; aromatic hydrocarbons such as toluene, o-, m- and p-xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, 1,2-dichloroethane and chlorobenzene; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol; C2-C4 alkanediols, such as ethylene glycol or propylene glycol; ketones such as acetone or 2-butanone; ether alkanols such as diethylene glycol; carboxylic esters such as ethyl acetate; N-methylpyrrolidone; dimethylformamide; and ethers, including open-chain and cyclic ethers, especially diethyl ester, methyl-tert-butyl-ether (MTBE), 2-methoxy-2methylbutane, cyclopentylmethylether, 1,4-dioxane, tetrahydrofuran and 2methyltetrahydrofuran, in particular tetrahydrofuran, MTB 2methyltetrahydrofuran. Mixtures of said solvents can also be used.

[00296] In another embodiment, the solvent is selected from dimethylformamide, N-methylpyrrolidone, toluene, xylene, monochlorobenzene or a mixture of two or more of them.

[00297] Preferred solvents are aromatic hydrocarbons, preferably toluene, 0-, m- and p-xylene, monochlorobenzene. In a preferred embodiment, the solvent is toluene.

[00298] In one embodiment, the ratio of volume of reagents to solvent is in the range of 1:40 to 1: 0.

[00299] In another embodiment, the ratio of volume of reagents to solvent is in the range of 1:40 to 1: 5.

[00300] In a preferred embodiment, the ratio in

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[00301] In a preferred embodiment, the volume ratio of reagents to solvent is in the range of 1:20 to 1:10, preferably 1: 5.

[00302] In a preferred embodiment, the compound of formula X is obtained in step (F) with> 95% enantiomeric excess.

[00303] In another embodiment of the invention, a process for the preparation of a compound of formula X that has low stereochemistry as in formula XR or a process for the preparation of a compound of formula X with enantiomeric excess of R enantiomer, or that is, compound XR,

^ Het xR where Het, R ¹ and R ^{2 are} as defined herein;

comprising at least the steps of, (A) reacting a compound of formula III,

THE

Jí w

Her

III where Het and W are as defined herein;

with M ² OR ^AC , where M ² and R ^AC are as defined herein;

to obtain the compound of formula IV,

wherein Het and R ^AC are as defined herein;

(B) hydrolysis of the compound of formula IV, as defined herein, in the presence of an acid or a base to obtain a compound of formula V,

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Ο

JÍ OH

Het

V where Het is as defined in the compound of formula IV;

(C) reacting the compound of formula V with X ¹ SO2NH2, where X ¹ is halogen;

to obtain the compound of formula VI,

where Het is as defined in the compound of formula V.

(D) hydrogenation of the compound of formula VI, in the presence of an MXLnCp * hydrogenation catalyst, where

M is rhodium, ruthenium, iridium, palladium, iron, platinum, or nickel,

and a hydrogen source selected from a) hydrogen, b) mixture of N (R) 3 where R is H or C 1 -C and alkyl HCOOH, c) HCOONa or HCOOK, d) mixture of C 1 -C alcohol and t-BuOK, t-BuONa or t-BuOLi, and e) combination of two or more from a) to d);

to obtain a compound of formula VII having low stereochemistry as in formula VII-R, O wz, ^U

HN- ^S x

^Het VII-R where Het is as defined in the compound of formula VI;

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53/61 (E) reacting the compound of formula VII-R with R ¹ NCS, where R ¹ is as defined herein, in the presence of a base, to obtain a compound of formula VIII having low stereochemistry as in formula VIII- R,

wherein Het and R ¹ are as defined in the compound of formula VIIR;

(D) reacting the compound of formula VIII-R with a compound of formula IX,

wherein LG and R ² are as defined herein, to obtain the compound of formula XR.

Examples

[00304] The characterization can be done by coupled high-performance liquid chromatography / mass spectrometry (HPLC / MS), gas chromatography (GC), by NMR or by their melting points.

[00305] HPLC method: Agilent Eclipse Plus C18, 150mmx4.6mm IDx5um.

[00306] Gradient A = 0.1% TFA in water, B = 0.1% TFA in acetonitrile.

[00307] Flow = 1.4 ml / min, oven temperature of the column = 30 ° C.

[00308] Gradient program = 10% B - 100% B - 5

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54/61 min, hold for 2 min, 3 min -10% B.

[00309] Running time = 10 min.

[00310] LCMS Method 1: C18 column (50 mm χ 3.0 mm χ 3μ).

[00311] Gradient A = 10 Mm of ammonium format in water,

B = 0.1% formic acid in acetonitrile.

[00312] Flow = 1.2 ml / min, oven temperature of the column = 40 ° C.

[00313] Gradient program = 10% B to 100% B in

1.5 min., Mater for 1 min at 100% B, 1 min at 10% B.

[00314] Execution time: 3.75 min.

[00315] Chiral HPLC method 1: ChiralPak IA column, 150 mm χ 4.6 mm χ 5μ.

[00316] Mobile phase A = heptane, B = isopropanol.

[00317] Flow = 1.0 ml / min, oven temperature of the column = 40 ° C.

[00318] Gradient program = 10% isocratic B; running time: 20 min.

[00319] Chiral HPLC method 3: ChiralPak IA column, 150 mm χ 4.6 mm χ 5μ.

[00320] Mobile phase A = heptane, B = isopropanol.

[00321] Flow = 1.0 ml / min, oven temperature of the column = 40 ° C.

[00322] Gradient program = 40% isocratic B; running time: 20 min.

[00323] ¹ H-NMR: The signals are characterized by the chemical displacement (ppm) versus tetramethylsilane, by their multiplicity and by their integral (relative number of hydrogen atoms given). The following abbreviations are used to characterize the multiplicity of signs: m =

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55/61 multiplet, q = quartet, t = triplet, d = doublet and s = singlet.

[00324] The abbreviations used are: h for hour (s), min for minute (s), rt for retention time and room temperature for 20 to 25 ° C.

[00325] The present invention is now illustrated in more detail by the following examples, without imposing any limitations on them.

[00326] With the appropriate modification of the starting materials, the procedures described in the examples below can be used to obtain other compounds of formula V, VI, VII, VIII or X.

Example 1: Preparation of (3R) -3- (2-chlorothiazol-5-yl) -8-methyl-7-oxo-6-phenyl-2,3dihydrothiazolo [3,2-a] pyrimidin-4-ium-5 -olate:

Step 1: Preparation of 2-chloro-N-methoxy-N-methyl-acetamide:

[00327] A 3-neck four-neck flask equipped with a Teflon blade stirrer, reflux condenser and thermal bag was loaded with N-methoxymethanamine hydrochloride (345 g), water (1.6 liter) and the reaction mixture resultant was cooled to 0 to -5 ° C. Then, potassium carbonate (1.466 g) was added in batches to the above reaction mixture, followed by the addition of methyl tert-butyl ether (1.4 liter). Chloroacetyl chloride (400 g) was dissolved in tert-butyl methyl ether (0.2 liter) and added dropwise to the reaction mixture maintained above at -5 ° C to 0 ° C and the reaction mixture was stirred for 2 h at 0 ° C. The reaction mixture was allowed to reach room temperature and two phases were separated. The organic layer was dried over sodium sulfate, filtered and evaporated to provide 2-chloro-N-methoxy-N-methyl-acetamide as a white solid (440 g, 90% yield and 98.0% area purity per HPLC).

Step 2: Preparation of 2-chloro-1- (2-chlorothiazol-5-yl) ethenone:

[00328] A 5-liter, four-neck flask equipped with a Teflon blade stirrer, reflux condenser and thermal bag was loaded with 2-chlorothiazole (250 g), THF (0.75 L) and the resulting reaction mixture was cooled to 0 to -5 ° C. Then, chloride was added

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56/61 lithium chloride isopropylmagnesium (1.929 L, 1.3 M solution in THF) over 0.5 h in the reaction mixture maintained above, at 0 to -5 ° C. The reaction mixture was then heated to 40 ° C and the reaction continued at 40 ° C for 2 h. The formation of chlorine- (2-chlorothiazol-5-yl) magnesium species was confirmed by extinguishing the small aliquot of the reaction mixture with iodine and monitoring the formation of 2-chloro-5-iodo-thiazole by GC analysis (conversion of 96% was observed by GC analysis). The reaction mixture was cooled to 0 to -5 ° C and the solution of 2chloro-N-methoxy-N-methyl-acetamide (343 g) in THF (0.25 L) was added dropwise. The reaction was continued from -5 to 0 ° C for 1 h and the progress of the reaction was monitored by HPLC. The reaction mixture was quenched with 1.5 N aq. of HCI solution (1 L) at -5 to 0 ° C and then warmed to room temperature. The two phases were separated and the aqueous phase extracted with methyl tert-butyl ether (2 x 300 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated to obtain a crude residue. The crude product was dissolved in methyl tert-butyl ether (0.7 L) at room temperature and activated carbon (4 g) and silica (80 g, 60-120 mesh) were added. The slurry was stirred for 0.5 h, filtered through a Buchner funnel and washed with methyl tert-butyl ether (0.3 L). The filtrate was evaporated to obtain 2-chloro-1- (2-chlorothiazol-5-yl) ethanone as a pale brown oil (409 g, 46% HPLC area purity).

Step 3: Preparation of r2- (2-CHLOROTHAZOL-5-iL) -2-oxo-ETiLl acetate:

[00329] A 0.25 L flask, with three necks, equipped with a teflon blade stirrer, reflux condenser and thermal bag was loaded with 2-chloro-1- (2-chlorothiazol-5-yl) ethanone (15g , 46% HPLC purity) and dimethylformamide 45 ml) at room temperature. Then, sodium acetate (12.55 g) was added in portions and the reaction was continued at room temperature for 4 h. The progress of the reaction was monitored by HPLC (> 95% conversion by HPLC). The reaction was quenched with water (50 ml) and extracted with methyl tert-butyl ether (3 x 100 ml). The two phases were separated and

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57/61 the combined organic phases were dried over sodium sulfate, filtered and evaporated to obtain a crude residue (17 g). The crude product was purified by column chromatography over silica gel to obtain [2- (2-chlorothiazol-5-yl) -2oxo-ethyl] acetate as a yellow solid (7.5 g).

Step 4: Preparation of 1- (2-chlorothiazol-5-yl) -2-hydroxy-ethanone:

[00330] A 250-ml, three-necked flask equipped with a magnetic stirrer, reflux condenser and thermal bag was charged with [2- (2-chlorothiazol-5-yl) -2-oxo-ethyl] acetate (7, 5 g) and 1 N HCI in MeOH (50 ml). The resulting solution was stirred for 5 h and the progress of the reaction was monitored by TLC. The methanol of the reaction mixture was distilled in vacuo and the crude residue obtained was purified by column chromatography to obtain 1 - (2-chlorothiazol-5-yl) 2-hydroxyethanone as a pale yellow solid (2.8 g, 84% HPLC area).

Step 5: Preparation of 4- (2-chlorothiazol-5-yl) -5H-oxathiazole 2,2DIOXIDE

[00331] A 100 ml bottle, three necks equipped with magnetic stirrer, reflux condenser and thermal bag was loaded with 1- (2-chlorothiazol-5-yl) -2-hydroxy-ethanone (1 g), toluene (20 mL), chlorosulfonamide (0.975 g) and p-toluenesulfonic acid (0.214 g). The resulting solution was heated to 100 ° C and stirred for 1 h. The progress of the reaction was monitored by HPLC (> 95% conversion). The reaction mixture was quenched with water and extracted with MTBE (15 mL x 2). The two phases were separated, the organic phase was evaporated and purified by 4- (2-chlorothiazol-5-yl) -5Hoxathiazole 2,2-dioxide column chromatography (0.42 g).

Step 6: Preparation of (4R) -4- (2-chlorothiazol-5-yl) oxathiazolidine 2,2-dioxide

A) Preparation of rhodium catalyst - RhClKR, R) -TsDPEN1Cp *:

[00332] A 250 ml flask, with three necks, equipped with

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58/61 teflon blade stirrer, nitrogen inlet and thermal bag was loaded with [RhCl2Cp *] 2 (2.0 g), (1 R, 2R) -Np-toluenesulfonyl-1,2-diphenylethylenediamine (2,38 g), dichloromethane (68 mL) and triethylamine (1.72 mL) under a nitrogen atmosphere. The resulting slurry was stirred for 0.5 h at 22-27 ° C and distilled water (40 ml) was added. The two phases were separated and the organic phase was washed with water (40 ml). The organic phase was dried over sodium sulfate, filtered and evaporated to obtain a brown solid residue. The brown residue was triturated with n-heptane (20 ml), filtered and dried under a nitrogen atmosphere to obtain RhCI [(R, R) -TsDPEN] Cp * as a red solid (3.4 g).

b) Preparation of the HCOOH-NEt3 mixture:

[00333] In a 2-liter 3-neck round bottom flask, formic acid (275 mL,> = 99% w / w) was added and cooled to 0 ° C. To this, 250 ml triethylamine,> = 99% w / w) was added slowly at 0 ° C and used immediately in reaction.

c) Preparation of (4R) -4- (2-chlorothiazol-5-yl) oxathiazolidine 2,2-dioxide:

[00334] A 100-ml, two-necked flask equipped with a magnetic stirrer, condenser and thermal bag was loaded with 4- (2-chlorothiazol5-yl) -5H-oxathiazole 2,2-dioxide (0.5 g) and dimethylformamide (15mL, 30V) was degassed with nitrogen for 10 min. Then, RhCI [(R, R) TsDPEN] Cp * (27 mg) was added followed by dropwise addition of HCOOH-NEta (2.5 mL, in a 5: 2 ratio). The resulting mixture was stirred for 2 h. HPLC showed> 97% conversion. The reaction mixture was quenched with water (15 ml) and extracted with methyl tert-butyl ether (3 x 50 ml). The combined organic phase was evaporated to obtain (4R) 4- (2-chlorothiazol-5-yl) oxathiazolidine 2,2-dioxide (500 mg; 90% HPLC area purity (rt = 3,645 min.),> 99 % ee by chiral HPLC method 1).

Step 7: Preparation of (4R) -4- (2-chlorothiazol-5-yl) -N-methylthiazolidin-2-imine

[00335] A 100 ml flask, with three necks, equipped

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59/61 with magnetic stirrer, reflux condenser and thermal bag was charged with (4R) -4- (2-chlorothiazol-5-yl) oxathiazolidine 2,2-dioxide (0.5 g, with 99% ee), ethanol (2 ml), methyl isothiocyanate (0.228 g) and triethylamine (0.56 ml) at room temperature. The resulting mixture was stirred for 14 h at 22-27 ° C. Then, the organic volatiles were removed under vacuum and sodium hydroxide (0.2 g) and water (2 ml) were added to the reaction flask. The reaction mixture was heated to 100 ° C and stirred for 2 h. The reaction was diluted with water (2 ml) and extracted with methyl tert-butyl ether (2 x 50 ml). The organic phases were dried over sodium sulfate and evaporated in vacuo to provide (4R) -4- (2chlorothiazol-5-yl) -N-methyl-thiazolidin-2-imine as brown oil [0.34 g, m / z = 234 amu (M + H ⁺ )] ·

Step 8: Preparation of (3R) -3- (2-chlorothiazol-5-yl) -8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo [3,2-aI pyrimidin-4-ium-5- olato:

[00336] A three-neck 50 ml flask equipped with magnetic stirrer, reflux condenser and thermal bag was charged with (E, 4R) -4- (2-chlorothiazol-5-yl) -N-methyl-thiazolidin-2 -imine (0.34 g) toluene (2 mL) and heated to 110 ° C under a nitrogen atmosphere. Then, bis (2,4,6-trichlorophenyl) 2-phenylpropanedioate (0.857 g) was added in batches to the reaction mass maintained at 110 ° C. After stirring at 110 ° C for 2 h, HPLC showed> 99% conversion. The reaction was cooled to below 50 ° C and the precipitated pale yellow solid was filtered through a sintered funnel and then the solid residue was washed with methyl tert-butyl ether (4 mL) and dried under vacuum to provide (3R) -3- (2-chlorothiazol-5-yl) -8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo [3,2-a] pyrimidin-4-ium-5-olate (110 mg, m / z = 378 amu (M + H ⁺ ) and 95.2% enantiomeric excess by the chiral HPLC method 3). ¹ H NMR (300 MHz, DMSO-d6): 3.42 (s, 3H), 3.94 (d, J = 12 Hz, 1H), 4.25-4.32 (m, 1 H), 6 , 48 (d, J = 8.1 Hz, 1 H), 7.06-7.11 (m, 1 H), 7.21 -7.26 (m, 2H), 7.6 (d, J = 7.5 Hz, 1H), 7.96 (s, 1H).

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60/61

Example 2: Preparation of (3R) -3- (2-chlorothiazol-5-yl) -8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo [3,2-a1pyrimidin-4-ium-5-olate :

Step 1: Preparation of (4R) -4- (2-chlorothiazol-5-yl) oxathiazolidine 2,2-dioxide

a) Preparation of the HCOOH-NEt3 mixture: prepared as described IN STEP 4 OF EXAMPLE 1.

b) Preparation of (4R) -4- (2-chlorothiazol-5-yl) oxathiazolidine 2,2-dioxide:

[00337] A 1L 3-necked round-bottom flask was loaded with 4- (2-chlorothiazol-5-yl) -5H-oxathiazole 2,2-dioxide (50g), dimethylformamide (100 ml), toluene (100 ml ) and degassed with nitrogen for 10 min. Then, the pentamethylcyclopentadienyl rhodium chloride dimer (120 mg) and (1R, 2R) -N-p-toluenesulfonyl-1,2-diphenylethylenediamine (136 mg) were added under a nitrogen atmosphere at room temperature. The resulting mixture was cooled to 0 to 5 ° C and freshly prepared HCOOH-NEta (12 ml, in a ratio of 1.1: 1) was added and stirred for 2 h. The reaction was monitored by HPLC and quenched with water (100 ml) and extracted with toluene (200 ml). The combined organic phase was washed with water (3 x 20 ml) and evaporated to obtain (4R) -4- (2-chlorothiazol-5-yl) oxathiazolidine 2,2-dioxide (49 g, 98% ee by the chiral HPLC method 1)

Step 2: Preparation of (4R) -4- (2-chlorothiazol-5-yl) -N-methylthiazolidin-2-imine

[00338] A 1 L three-neck flask equipped with magnetic stirrer, reflux condenser and thermal bag was loaded with (4R) -4- (2-chlorothiazol-5-yl) oxathiazolidine 2,2-dioxide (49 g, with 98% ee), ethanol (196 ml), methyl isothiocyanate (22.5 g) and triethylamine (56 ml) at room temperature. The resulting mixture was stirred for 14 h at 22-27 ° C. Then, the organic volatiles were removed under vacuum and sodium hydroxide (0.2 g) and water (2 ml) were added to the reaction flask. The reaction mixture was

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61/61 heated to 70 ° C and stirred for 2 h. The reaction was diluted with water (2 ml) and extracted with toluene (2 x 500 ml). The organic phases were dried over sodium sulfate and evaporated in vacuo to provide (4R) -4- (2-chlorothiazol-5-yl) -Nmethyl-thiazolidin-2-imine as brown oil [44.7 g, m / z = 234 amu (M + H ⁺ )].

Step 3: Preparation of (3R) -3- (2-chlorothiazol-5-yl) -8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo [3,2-a1pyrimidin-4-ium-5-olate :

[00339] A 500 ml flask, with three necks, equipped with magnetic stirrer, reflux condenser and thermal bag was loaded with (E, 4R) -4- (2-chlorothiazol-5-yl) -N-methyl-thiazolidin -2-imine (35 g), toluene (70 mL) and heated to 80 ° C under nitrogen atmosphere. Then 2 (bis (4-chlorophenyl) phenylpropanedioate) (60 g) was dissolved in toluene (70 ml) at 45 ° C and added dropwise to the reaction mass maintained at 80 ° C. 100 ° C for 1 h, HPLC showed> 99% conversion.The reaction was cooled below 50 ° C and the precipitated pale yellow solid was filtered, washed with toluene (3 x 70 mL) and dried under vacuum to provide ( 3R) -3- (2-chlorothiazol-5-yl) -8methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo [3,2-a] pyrimidin-4-ium-5-olate as 1 ^s lot (29 g, m / z = 378 amu (M + H ⁺ ) and 99% enantiomeric excess by the chiral HPLC 3 method); The combined mother liquor was transferred to the reactor, acetone (105 ml) was added and stirred at 22-27 ° C for 1 h The precipitated pale yellow solid was filtered and washed with toluene (70 ml x 3) to obtain (3fi) -3 (2-chlorothiazol-5-yl) -8-methyl-7- oxo-6-phenyl-2,3-dihydrothiazolo [3,2-a] pyrimidin-4-ium5-olate as 2 ^S lot (13 g, 99% in area of HPLC purity and 98.7% of enantiomeric excess by chiral method by HPLC 3).

Claims (15)

1. PROCESS FOR PREPARING Pyrimidinium COMPOUND containing S of formula X THE

on what C * is an asymmetric carbon atom of S or R configuration; R ¹ is C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, or -CH2phenyl, which are groups unsubstituted or substituted by halogen or C1-C4 alkyl; R ² is a 5- or 6-membered saturated, partially unsaturated or aromatic carbo- or heterocyclic ring, where the ring is unsubstituted or substituted by R ^2a ; Het is selected from D-1, D-2 and D-3:

D-1 D-2 D-3 where R ^a is each independently R ^a is halogen, C1C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, or phenyl; n is 0, 1 or 2; and # denotes the bond in formula X; R ^2a is halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OR ^C , C (= O) OR ^C , C (= O) NR ^b R ^c , phenyl, or pyridyl, 0 which is unsubstituted or substituted by halogen, C1-C6 haloalkyl or Ci-Ce haloalkoxy; Petition 870190110600, of 10/30/2019, p. 115/124 2/7

R ^b is hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy; R ^c is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, Ci-Ce cycloalkyl; wherein two geminally bonded groups R ^and R ^b together with the atom to which they are attached, can form a 3- to 7-membered, saturated, partially unsaturated or aromatic heterocyclic ring; characterized by comprising at least the step of (E) reacting the compound of formula VII, ⁰ the HN ^ ^S x H Het in that C * is an asymmetric carbon atom of S or R configuration; Het is as defined in the compound of formula X; with R ¹ NCS, where R ¹ is C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl or -CH2-phenyl, where the groups are unsubstituted or substituted by halogen or C1-C4 alkyl; in the presence of a base, to obtain a compound of formula VIII, rL Jl S NH SL _t ^Vl H Het in that C * and Het are as defined in the compound of formula VII; R ¹ is as defined herein. 2. PROCESS, according to claim 1, characterized by still comprising at least the steps of, Petition 870190110600, of 10/30/2019, p. 116/124 3/7 (A) reacting a compound of formula III, THE JL w Her III in which W is halogen, O-p-toluenesulfonyl, O-methanesulfonyl, or Otrifluoromethanesulfonyl; Het is as defined in the compound of formula X in claim 1; with M ² OR ^AC where M ² is selected from lithium, sodium, potassium, aluminum, barium, cesium, calcium and magnesium; R ^AC is C (= O) -C1-C4 alkyl; to obtain the compound of formula IV, THE 1oR ^AC Her IV where Het and R ^AC are as defined herein; (B) hydrolyze the compound of formula IV, as defined herein, in the presence of an acid or a base to obtain a compound of formula V, O JL OH Her V where Het is as defined in the compound of formula IV; (C) reacting the compound of formula V with X ² SO2NH2, where X ² is halogen, to obtain the compound of formula VI θ O Wz. ^U a / ° Het ^^ ⁷ VI where Het is as defined in the compound of formula V; (D) hydrogenate the compound of formula VI, in the presence of an MXLn (q-arene) m hydrogenation catalyst Petition 870190110600, of 10/30/2019, p. 117/124 4/7 where M is a transition metal from group VIII to group XII of the periodic table; X is an anion; m is 0 or 1; Ln is Ln1 or Ln2, where Ln1 is a chiral ligand of the formula Ln1, H R ¹² I ^ R ¹⁰ R ⁶ ^ NH ₂ H Ln1 where C * is an asymmetric carbon atom of S or R configuration; R ¹⁰ is OH or NH-SO2-R ¹¹ ; R ¹¹ is unsubstituted or substituted aryl, independently of one another with halogen, C1-C10 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, SO3H, or SOsNa; or R ¹¹ is C1-C10 perfluoroalkyl, or R ¹³ R ¹⁴ N, where R ¹³ and R ¹⁴ independently represent unsubstituted or substituted C1-C10 alkyl by Ce-Cw aryl or R ¹³ and R ¹⁴ each independently represent a cycloalkyl group Ce-Cw; R ¹² independently represents aryl ring or cycloalkyl ring C6-C10, where the ring is unsubstituted or substituted independently of one another by halogen, C1-C10 alkyl, C1-C10 alkoxy, C1-C4 alkoxy, C3Ce cycloalkyl, SO3H, or SOsNa, or both R ¹² are linked between itself to form a ring Petition 870190110600, of 10/30/2019, p. 118/124 5/7 carbocyclic with 3 to 6 members or a carbocyclic ring with 5 to 10 members partially unsaturated; Ln2 is a chiral phosphorus linker; and a hydrogen source selected from a) hydrogen, b) mixture of N (R) 3 where R is H or C 1 -C and alkyl HCOOH, c) HCOONa or HCOOK, d) mixture of C 1 -C alcohol and t-BuOK, t-BuONa or t-BuOLi, and e) combination of two or more from a) to d); to obtain a compound of formula VII, The 0 hnX H Het in that C * is an asymmetric carbon atom of S or R configuration; Het is as defined in the compound of formula VI. PROCESS, according to claim 1, characterized in that it further comprises the step (F) of reacting the compound of formula VIII with a compound of formula IX,

on what, LG is an output group selected from halogen, OR ^U and SR ^U ; on what R ^u is Ci-Ce alkyl or aryl, which is unsubstituted or substituted by halogen; R ² is as defined in the compound of formula X in claim 1; to obtain the compound of formula X as defined in claim 1. 4. PROCESS, according to claim 2, Petition 870190110600, of 10/30/2019, p. 119/124 6/7 characterized by the η-arene being an aryl ring which is unsubstituted or substituted by C1-C4 alkyl. PROCESS according to either of claims 2 or 4, characterized in that η-arene is selected from benzene, p-cymene, mesitylene, 1,3,5-triethylbenzene, hexamethylbenzene, anisole, 1,5-cyclooctadiene, cyclopentadienyl (Cp), norbornadiene, and pentamethylcyclopentadienyl (Cp *). PROCESS according to either of claims 2 or 4, characterized in that MXLn (q-arene) m in step (D) is MXLnl (q-arene) m where R ¹⁰ is NH-SO2-R ¹¹ ; and R ¹² and R ¹¹ are independently phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, SO3H, and SOsNa. PROCESS according to any one of claims 2, 4, and 6, characterized in that MXLn (q-arene) m in step (D) is MXLnl (q-arene) m in which X is a halide; R ¹² is independently phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl or 4-methoxyphenyl; R ¹⁰ is NH-SO2-R ¹¹ , and SO2-R ¹¹ is p-toluenesulfonyl, methanesulfonyl, 4-benzenesulfonyl, or pentafluorophenylsulfonyl. 8. PROCESS according to any one of claims 2,4, 6 and 7, characterized in that m is 1 and MXLn (q-arene) m in step (D) is of formula MXLnCp *, in which M is rhodium, ruthenium , iridium, palladium, iron, platinum or nickel

Petition 870190110600, of 10/30/2019, p. 120/124 7/7 9. PROCESS, according to any one of claims 2, 4, and 6 to 8, characterized by the Mn step (D) being rhodium, ruthenium, or iridium. 10. PROCESS, according to claim 1, characterized in that the base in step (E) is selected from triethylamine, diisopropylethyl amine, tri-n-butylamine, sodium hydroxide, and potassium hydroxide. 11. PROCESS according to any one of claims 1, characterized by R ¹ is C1-C4 alkyl, C3-C6 cycloalkyl or C2-C4 alkenyl, which is unsubstituted, or substituted by halogen. 12. PROCESS, according to claims 1 or 3, characterized by R ² is phenyl, pyridinyl or thiophenyl, which is unsubstituted or substituted by R ^2a . 13. PROCESS, according to claim 1, characterized by R ^to be halogen or C1-C4 haloalkyl. 14. PROCESS, according to claim 1, characterized by Het being D-2, where n is 0 and R ^a is halogen. 15. OPTICALLY ACTIVE COMPOUND of formula VII, characterized by being the ⁰ Jθ ^H JT O Het * _VN where C * is an asymmetric carbon atom of S or R configuration; and wherein Het is D-2 or D-3 as defined in claim 1.